Amino acid derivatives, processes for the manufacture thereof and pharmaceutical compositions (II) containing these compounds

ABSTRACT

The invention relates to new amino acid derivatives of general formula I R1-R11-A1B(I) and the pharmaceutically acceptable salts thereof, wherein group B is -A2-NR2R3 or R5, and wherein R1, A1, A2, R2, R3, R5 and R11 have the meanings described in the specification, as well as the preparation and use thereof. The novel compounds are valuable neurokinin (tachykinin) antagonists.

This application is a continuation of prior pending application Ser. No.08/434,613, filed May 4, 1995.

The invention relates to new amino acid derivatives of general formulaI,

    R.sup.1 --R.sup.11 --A.sup.1 --B                           (I)

wherein B represents the group --A² --NR² R³ or R⁵, and thepharmaceutically acceptable salts thereof, processes for theirpreparation and pharmaceutical compositions containing these compounds.The compounds are valuable neurokinin (tachykinin)-antagonists.

European Patent Applications EP 394 989 and EP 443 132 as well as WO94/05 693 disclose peptides with a neurokinin-antagonistic activity. Thecompounds according to the invention differ significantly from thesepeptides in the members R¹, A², R⁵ and ##STR1##

The abbreviations used for the amino acids in this specification and theClaims correspond to the conventional three letter code described forexample in Europ. J. Biochem., 138, 9 (1984). The other abbreviationsare defined as follows:

Boc=t-Butoxycarbonyl

Bzl=Benzyl

CDI=Carbonyldiimidazole

Cha=3-Cyclohexylalanine

DCCI=Dicyclohexylcarbodiimide

DCH=Dicyclohexylurea

HOBt=1-Hydroxybenzotriazole

Hpa=Homophenylalanine

Hyp=(2S,4R)-Hydroxyproline

Pal=3-(1-Pyrrolyl)alanine

THF=Tetrahydrofuran

TFA=Trifluoroacetic acid

Z=Benzyloxycarbonyl

Me=Methyl

Ac=Acetyl

Et=Ethyl

DMF=Dimethylformamide

DPPA=Diphenylphosphorylazide

PPA=Polyphosphoric acid

RT=ambient temperature

Mtr=4-Methoxy-2,3,6-trimethylbenzolsulphonyl

Trp(for)=formyl-protected Tryptophan

Met(O)=Methionine, wherein S is oxidized to form sulphoxide

Bum=N(II)-tert. butoxymethyl

Unless explicitly indicated otherwise in the following text, theexpression amino acid covers natural and unnatural amino acids, both theD- and L-forms, more particularly α-amino acids as well as the isomersthereof.

If an amino acid is given without prefix (e.g. Orn) this indicates theL-form of the amino acids. The D-form is explicitly indicated.

A simplified form is used for the illustration of the formulae. In thisillustration of the compounds, all CH₃ -substituents are represented bya single bond, for example ##STR2##

In the illustration of groups (e.g. R¹ or A²), the CH₃ -- groups in thegroup are written in full. It is only in the groups derived fromcamphorcarboxylic acid and the derivatives thereof that the CH₃ -groupsbonded to the bridging carbon atom are represented by single bonds, forexample group (R¹) ##STR3##

The invention relates to new amino acid derivatives of general formula I

    R.sup.1 --R.sup.11 --A.sup.1 --B                           (I)

and the pharmaceutically acceptable salts thereof, wherein

R¹ is a saturated or partially saturated 6-membered ring which consistsof 6 carbon atoms or 5 carbon atoms and an O- or N-atom and which has,in the 2- or 3-position relative to R¹¹, an oxygen functionality whichis ═O, --OH or --O-(C₁ -C₄ -alkyl), whilst the ring may also have a--CH₂ --, --C (CH₃)₂ --, --C(C₂ H₅)₂ -- or --CH₂₋ CH₂ -- bridge, or,additionally to said bridge, may have a bond between two non-adjacentcarbon atoms, and the un-bridged or bridged ring may also be substitutedby 1 to 5 (C₁ -C₃)-alkyl groups;

R¹¹ denotes --C(O)--, --CH₂ --C(O)--, --SO₂ -- or --CH₂ --SO₂ --;

A¹ is D- or L-alanine (Ala), D- or L-valine (Val), D- or L-leucine(Leu), D- or L-isoleucine (Ile), D- or L-serine (Ser), D- or L-threonine(Thr), D- or L-allothreonine, D- or L-cysteine (Cys), D- or L-methionine(Met), D- or L-phenylalanine (Phe), D- or L-tryptophan (Trp), N-formylprotected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- orL-didehydroproline (ΔPro) such as 3,4-didehydroproline (Δ(3,4)-Pro), D-or L-hydroxyproline (Pro(OH)) such as 3-hydroxyproline (Pro(30H)) and4-hydroxyproline (Pro(40H)), D- or L-azetidine-2-carboxylic acid (Azt),D- or L-thioproline (Tpr), D- or L-aminoproline (Pro(NH₂)) such as3-aminoproline (Pro(3NH₂)) and 4-aminoproline (Pro (4NH₂)), D- orL-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- orL-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- orL-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine(Gln), D- or L-asparagine (Asn), D- or L-lysine (Lys), D- or L-arginine(Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L-hydroxypiperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylicacid, D- or L-mercaptoproline (Pro(SH)) such as 3-mercaptoproline(Pro(3SH)) and 4-mercaptoproline (Pro(4SH)), Tpr(O), Met(O), Tpr(O₂) orMet(O₂), and the geometric isomers thereof, whereby the hydroxy andamino groups contained therein may be protected by standard protectinggroups (e.g. acyl, carbamoyl or aralkyl (in particular benzyl));

B is group --A² --NR² R³ or --R⁵ ;

A² is a lipophilic α-amino acid which contains a phenyl, mono-, di- ortri-substituted phenyl, heteroaryl, cyclohexyl or cyclopentyl group, anaphthyl group or a mono- or di-C₁₋₃ -alkylamino group, and this cyclicgroup or amino group is separated by a 1- to 8-membered chain from thebackbone of the amino acid, whereby the substituents of the phenyl groupmay, independently of each other, be halogen, trihalomethyl, alkoxy,alkyl, cyano or 1-pyrrolidinyl and whereby in the 1- to 8-memberedchain, the members of the chain may be --CHR⁴, --C(O)--, --O--, --S--and/or --NR⁴ -- which are arranged such that they result in one of thefollowing three types of chains

    --(CHR.sup.4).sub.1-8 --

    --(CHR.sup.4).sub.0-p --G.sup.1 --(CHR.sup.4).sub.0-q --

    (--CHR.sup.4).sub.1-p --G.sup.2 --(CHR.sup.4).sub.0-q --

wherein G¹ is --C(O)O-- or --C(O)--NR⁴ --, G² is --O--, --S--, --NR⁴--C(O)--O--, --NR⁴ --C(O)--, --NR⁴ --C(O)--NR⁴ -- or --O--C(O)--NR⁴ --and p and q are whole numbers from 1 to 6 which are chosen such that thetotal number of the chain members is 1 to 8,

and R⁴ is hydrogen, alkyl, aryl or aralkyl, wherein aryl is phenyl,mono-, di- or tri-substituted phenyl or naphthyl; the substituents ofthe phenyl group are, independently of each other, halogen,trihalomethyl, alkoxy, alkyl or cyano, and the alkyl group contains 1 to3 carbon atoms; (whereby, if one chain contains more than one --CHR⁴-group, R⁴ can only be alkyl, aryl or aralkyl in one of these --CHR⁴-groups)

or A² is Leu, Ile, Nle, Val, Met or one of the groups ##STR4## (whereinx and y independently of each other are 1 or 2);

R² and R³ independently of each other are alkyl, arylalkyl, heteroarylor hydroxy (wherein aryl is phenyl, mono-, di- or trisubstituted phenylor naphthyl; the substituents of the phenyl group are, independently ofeach other, halogen, trihalomethyl, alkoxy, alkyl, alkylthio, hydroxy,nitro, trifluoromethoxy, dialkylamino or cyano or 2 adjacent positionsof the phenyl group are linked by --O--(CH₂)₁ or 2 --O--; heteroaryl isindolyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl oralkoxy group contains 1 to 3 carbon atoms) or the group ##STR5## is aring of general formula ##STR6## wherein m and n are each 0, 1, 2 or 3,whereby the sum thereof is 2, 3, 4 or 5,

s is 2 or 3,

W is the group ##STR7## (CH₂)₀₋₂ -aryl, CH(aryl)₂, cyclopentyl, (CH₂)₀₋₂-cyclohexyl, pyridyl or ##STR8## (wherein aryl is phenyl, mono-, di- ortrisubstituted phenyl or naphthyl; the substituents of the phenyl groupindependently of each other are halogen, trihalomethyl, alkoxy, alkyl,cyano, hydroxy, nitro, --CO₂ CH₃, --CO₂ C₂ H₅, or alkylthio, or 2adjacent positions of the phenyl group are linked by --O--(CH₂)₁₋₂ --O--and alkyl contains 1 to 3 carbon atoms );

R⁵ is an amine of formula ##STR9## wherein

R⁶ is aralkyl, diarylalkyl (in these groups aryl is phenyl or naphthyland alkyl is (C₁₋₅)alkyl), heteroaryl-(C₁₋₅)alkyl (wherein heteroaryl is2-, 3- or 4-pyridyl or 2- or 3-thienyl), phenylamino-(C₁₋₅)alkyl,naphthylamino-(C₁₋₅)alkyl or N-phenylalkylpiperidinyl (wherein thephenyl groups listed are unsubstituted or have 1, 2 or 3 substituentswhich are, independently of each other, (C₁₋₅)alkyl, preferably methyl,(C₁₋₅)alkoxy, preferably methoxy, dimethylamine, halogen,trifluoromethyl, --CN or --OCF₃);

R₇ is hydrogen or (C₁₋₅)-alkyl;

X is O or H₂ ;

Y and Z independently of each other are hydrogen, (C₁₋₅)alkyl;(C₁₋₅)alkyloxy, benzyloxy (wherein the phenyl group is unsubstituted orhas 1, 2 or 3 substituents which are independently of each other(C₁₋₅)alkyl, preferably methyl, (C₁₋₅)alkoxy, preferably methoxy,dimethylamine, halogen, trifluoromethyl, --CN or --OCF₃), --OCF₃,halogen, --CF₃, --CN, --CH₂ NH₂, --CONH₂, N-(C₁₋₄ -alkyl)₂,NH-(C₁₋₄)alkylcarbonyl, N-(C₁₋₅)alkyl-N-(C₁₋₄)alkylcarbonyl, NH₂ orNH-(C₁₋₅)alkyl or if Y and Z are in a vicinal position to one another,both together represent --OCH₂ O--, --OCH₂ CH₂ O-- or (CH)₄ ;

t and u have one of the following meanings

(a) t and u are zero

(b) t is one and u is zero

(c) t and u are both one

(d) t is two and u is zero;

and if t is one and u is zero, R⁵ is also an amine of formula IV##STR10## wherein

R⁶, R⁷, Y and Z have the above meanings and

R⁸ is hydrogen and R⁹ is hydroxy, (C₁₋₅)alkoxy, phenyl-(C₁₋₅)alkyloxy,naphthyl-(C₁₋₅) alkyloxy or (C₁₋₄) alkylcarbonyl, or wherein

R⁸ and R⁹ together are oxygen or --OCH₂ CH₂ O--;

and the chirality of C* may be R or S.

The compounds according to the invention are valuable neurokinin(tachykinin)-antagonists which have substance P-antagonism, but alsoneurokinin A and neurokinin-B antagonistic properties. They are usefulfor treating and preventing neurokinin-mediated diseases.

Compounds of general formula I may have acid groups, mainly carboxylgroups or phenolic hydroxy groups, and/or basic groups such as guanidinoor amino functionalities. Therefore, compounds of general formula I maybe present either as internal salts, as salts with pharmaceuticallyacceptable inorganic acids such as hydrochloric acid, sulphuric acid,phosphoric acid, sulphonic acid or organic acids (e.g. maleic acid,fumaric acid, citric acid, tartaric acid or acetic acid) or as saltswith pharmaceutically acceptable bases such as alkali or alkaline earthmetal hydroxides or carbonates, zinc or ammonium hydroxides or organicamines such as diethylamine, triethylamine, triethanolamine and thelike.

The chiral centres in the new amino acid derivatives may have an R--, S-or R,S-configuration.

The expression "partially saturated 6-membered ring" used in thedefinition of R¹ represents a 6-membered ring which contains two doublebonds or preferably one double bond.

The bridged or unbridged ring described in the definition of R¹ maycontain 1 to 5 (C₁ -C₃)-alkyl groups (preferably methyl groups). Here,it must be noted that each of these alkyl groups substitutes for one ortwo H-atoms of the CH₂ -groups forming the ring, and that in twoadjacent CH₂ -groups a maximum of 3 H-atoms is substituted by alkylgroups. This means that the group R¹ contained in e.g. compound 1 has amaximum of 5 alkyl groups in the ring (in addition to the two methylgroups of the bridge) and that the group R¹ in compound 22, has amaximum of 4 alkyl groups.

The above bridge preferably connects positions 1 and 4, 2 and 5 orespecially 3 and 6, based on position 1 of the ring being bonded to R¹¹.

Preferably, the bridge connects 2 carbon atoms of the ring. If R¹ is aheterocyclic ring containing N, R¹ is preferably bonded to R¹¹ via acarbon atom.

The expression "heteroaryl group" contained in the definition of A²represents a mono-, bi- or tricyclic aromatic ring system which contains1 or 2 heteroatoms, namely one or two nitrogen atoms or one nitrogenatom and one sulphur atom. The group may optionally contain 1 or 2substituents (C₁₋₃ alkyl) or one oxo group or one alkoxy group.

Examples of suitable heteroaryl groups are ##STR11##

It must be noted that the above heteroaryl groups may also be bound tothe chain in positions other than those mentioned.

As mentioned above, the "1- to 8-membered chain" contained in A²comprises 1 to 8 members denoting the following groups: --CHR⁴ --,--C(O)--, --O--, --S--, --NR⁴ --. The chain is bound to the α-carbonatom of the amino acid (A²).

R⁴ represents (as indicated above) hydrogen, alkyl, aryl or aralkyl. R⁴is preferably hydrogen, methyl or phenyl.

Examples of suitable chains are

--(CH₂)₁₋₄ --

--CH₂ --O--CH₂ --, --CH₂ --O--

--CH₂ --S--CH₂ --, --CH₂ --S--

--CH(CH₃)--O--CH₂ --, --CH(CH₃)--O--

--(CH₂)₁₋₂ --C(O)--O--CH₂ --, --C(O)--NH--

--(CH₂)₄ --NH--C(O)--O--CH₂ --

--CH₂ --C(O)--NH--

--CH₂ --C(O)--NH--CH₂ --

--CH₂ --C(O)--N(CH₃)--CH₂ --

--CH₂ --C(O)--O--

--CH₂ --NH--C(O)--CH₂ --

--CH₂ --NH--C(O)--O--

--CH₂ --NH--C(O)--O--CH₂ --

--CH₂ --NH--C(O)--NH--

--(CH₂)₂ --C(O)--NH--(CH₂)₂ --

--(CH₂)₄ --NH--C(O)--CH₂ --

--(CH₂)₃ --NH--C(O)--O--CH₂ --

The chain contains preferably 1 to 5, more preferably 1 to 4 members.

Those compounds of formula I, according to the invention, are preferred,wherein

R¹ and R¹¹ have the above meanings,

A¹ is D- or L-alanine (Ala), D- or L-valine (Val), D- or L-leucine(Leu), D- or L-isoleucine (Ile), D- or L-serine (Ser), D- or L-threonine(Thr), D- or L-allothreonine, D- or L-cysteine (Cys), D- or L-methionine(Met), D- or L-phenylalanine (Phe), D- or L-tryptophan (Trp), N-formylprotected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- orL-didehydroproline (ΔPro) such as 3,4-didehydroproline (Δ(3,4)-Pro), D-or L-hydroxyproline (Pro(OH)) such as 3-hydroxyproline (Pro(30H)) and4-hydroxyproline (Pro(40H)), D- or L-azetidine-2-carboxylic acid (Azt),D- or L-thioproline (Tpr), D- or L-aminoproline (Pro(NH₂)) such as3-aminoproline (Pro(3NH₂)) and 4-aminoproline (Pro(4NH₂)), D- orL-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- orL-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- orL-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine(Gln), D- or L-asparagine (Asn), D- or L-lysine (Lys), D- or L-arginine(Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L-hydroxypiperidine carboxylic acid such as 5-hydroxypiperidine-2-carboxylicacid, D- or L-mercaptoproline (Pro(SH)) such as 3-mercaptoproline(Pro(3SH)) and 4-mercaptoproline (Pro(4SH)), Tpr(O), Met(O), Tpr(O₂) orMet(O₂), and the geometric isomers thereof, whereby the hydroxy andamino groups contained therein may be protected by standard protectinggroups (e.g. acyl, carbamoyl or aralkyl (in particular benzyl));

and if B is group --A² --NR² R³

A² is a lipophilic amino acid which contains a phenyl-, mono-, di- ortrisubstituted phenyl-, heteroaryl-, cyclohexyl- or cyclopentyl group ora mono- or di-C₁₋₃ -alkylamino group, and this cyclic group or aminogroup is separated by a 1- to 8-membered chain from the backbone of theamino acid (whereby the substituents of the phenyl group independentlyof each other are halogen, trihalomethyl, alkoxy, alkyl, cyano or1-pyrrolidinyl and the chain is defined as in claim 1) or A² is Leu,Ile, Nle, Val, Met or one of the groups ##STR12## (wherein x and yindependently of each other are 1 or 2);

R² and R³ independently of each other are alkyl, arylalkyl, heteroarylor hydroxy (wherein aryl represents phenyl, mono-, di- or trisubstitutedphenyl or naphthyl; the substituents of the phenyl group independentlyof each other denote halogen, trihalomethyl, alkoxy, alkyl or cyano;heteroaryl represents indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl;and the alkyl or alkoxy groups contains 1 to 3 carbon atoms) or thegroup ##STR13## is a ring of general formula ##STR14## wherein m, n ands are defined as in claim 1 and

W is the group ##STR15## --(CH₂)₀₋₂ -aryl, CH(aryl)₂, cyclopentyl or(CH₂)₀₋₂ -cyclohexyl (wherein aryl represents phenyl, mono-, di- ortrisubstituted phenyl or naphthyl; the substituents of the phenyl groupindependently of each other are halogen, trihalomethyl, alkoxy, alkyl orcyano).

Of the compounds, according to the invention, of formula Ia

    R.sup.1 --R.sup.11 --A.sup.1 --A.sup.2 --NR.sup.2 R.sup.3  Ia

those are preferred wherein

R¹ and R¹¹ have the above meanings and/or

A¹ is an amino acid which carries one or 2 polar functional group(s) inthe side chain such as OH, COOH, NH₂, guanidine, CONH₂, SH; particularlywherein

the functional group in the side chain of A¹ is OH and/or wherein A¹ isPro, 4-hydroxyproline, 3-hydroxyproline, Ser, Thr, Trp(For) or Tyr;preferably 4-hydroxyproline with 2-S-configuration, particularly##STR16## and/or wherein A² represents an acyclic or cyclic amino acidsuch as (O-benzyl)Ser, (O-subst. benzyl)Ser, (O-benzyl)Thr,cyclohexylalanine, homophenylalanine, 3-(1-pyrrolyl)-alanine,3-(2,5-dimethyl-1-pyrrolyl)alanine, 3-(1-indolyl)alanine,2-amino-4-(1-pyrrolyl)-butyric acid, 2-amino-5-(1-pyrrolyl)valeric acid,2-amino-6-(1-pyrrolyl)caproic acid, Leu, Lys(Z), 3-(2-thienyl)alanine,3-(3-benzothienyl)alanine, 3(1-isoindolinonyl)alanine, (O-benzyl)Asp,(O-benzyl)Glu, Trp, (N-Me)Trp, His, 3-(2-thiazolyl)-alanine, or3-dimethylamino-alanine, -(O-methyl)Tyr, 2-naphthylalanine, ##STR17##wherein the phenyl groups contained in the amino acids may be mono-, di-or tri-substituted and the substituents independently of each other arehalogen, trihalomethyl, alkoxy, alkyl or cyano, the alkyl or alkoxygroup contains 1 to 3 carbon atoms;

and wherein the above amino acids are preferably present inS-configuration;

special mention must be made of compounds wherein

A² is ##STR18## or preferably ##STR19## and/or wherein R² and R³independently of each other represent methyl, benzyl, phenethyl (whereinthe phenyl groups contained therein are substituted by one or two methylor methoxy groups) or pyridylmethyl;

preferably a compound wherein R² is methyl and R³ is benzyl oralkoxybenzyl, more particularly wherein R³ is 2-methylbenzyl; or whereinthe group ##STR20## represents a ring ##STR21## wherein m is 1 and n is1 or 2;

or wherein the group ##STR22## is a ring ##STR23## wherein s is 2 or 3(preferably 2) and W is as hereinbefore defined;

preferably wherein W is cyclohexyl, phenyl, CH(phenyl)₂, naphtyl orpyridyl, wherein the phenyl groups are substituted;

wherein if W is phenyl, this is preferably monosubstituted by --CO₂ CH₃,--CO₂ C₂ H₅, halogen, alkoxy, alkyl, cyano, hydroxy, nitro or alkylthio,particularly by methoxy, chlorine, methyl, ethyl, cyano, hydroxy, nitroor methylthio, preferably by methoxy, chlorine, methyl, cyano ormethylthio, wherein the substituent of the phenyl group is preferably inposition 2 and

if W represents the group --CH(phenyl)₂, the phenyl groups aresubstituted by one halogen each, preferably by fluorine, wherein in the--CH(phenyl)₂ group the two phenyl groups are preferably substitutedidentically, preferably in p-position.

Of the compounds, according to the invention, of formula Ib

    R.sup.1 --R.sup.11 --A.sup.1 --R.sup.5                     Ib

those are preferred wherein

R¹ and R¹¹ have the above meanings and/or

A¹ is an amino acid which carries one or 2 polar functional group(s) inthe side chain such as OH, COOH, NH₂, guanidine, CONH₂, SH; particularlywherein

the functional group in the side chain of A¹ represents OH and/orwherein A¹ is Pro, 4-hydroxyproline, 3-hydroxyproline, Ser, Thr,Trp(For) or Tyr; preferably 4-hydroxyproline with 2-S-configuration,particularly ##STR24##

Of the compounds according to the invention, those are preferred whereinR⁵ is a group of general formula II ##STR25## particularly those whereint is one and u is zero or t is two and u is zero or t and u are both oneand R⁶, R⁷, X, Y and Z are specified as hereinbefore.

Special mention must be made of those compounds wherein R⁶ is benzyl ormethoxybenzyl and/or wherein R⁷ is hydrogen and/or wherein X is oxoand/or wherein Y and Z independently of each other represent methoxy,hydrogen, CF₃ or tert.butyl or together represent --(CH)₄ --.

Of the above compounds those are preferred wherein R¹ is ##STR26##preferably ##STR27## and R¹¹ is --CH₂ SO₂ -- or preferably --C(O)--. Theabove amino acids are preferably in the S-configuration.

Test results of the compounds according to the invention:

The receptor affinity at the NK₁ -receptor (substance P-receptor) wasdetermined with cloned NK₁ -receptors on human lymphoblastoma cells(IM-9), whereby the displacement of ¹²⁵ I-labelled substance P ismeasured. The NK₂ -binding test is carried out on transfixed A20 cellswhich represent the human NK₂ receptor. The displacement of ¹²⁵I-BN-neusolinine A is determined. The IC₅₀ -values thus obtained are:

    ______________________________________                                        Compound       NK.sub.1  nm!                                                                          NK.sub.2  nM!                                         ______________________________________                                        1              3.1      21                                                    2              3.6      21                                                    3              3.0      65                                                    4              5.0      110                                                   5              11       117                                                   6              45                                                             7              0.45     44                                                    8              3.0      18                                                    9              17                                                             10             200                                                            11             3.2                                                            12             5.6                                                            13             105      780                                                   14             3.1      240                                                   15             3.2      38                                                    16             0.7      19                                                    17             7        93                                                    18             8        16                                                    19             26       600                                                   20             26       350                                                   21             20       130                                                   22             25       1300                                                  23             14       140                                                   24             3.3      1240                                                  25             18.0     880                                                   26             28                                                             27             0.5      450                                                   28             23       1500                                                  42             1.2      54                                                    43             1.2      21                                                    44             5.1      39                                                    45             4.9      59                                                    47             3.2      57                                                    ______________________________________                                    

List of Compounds: ##STR28##

The compounds 56 and 57 contain groups R¹ (again in a simplified form ofillustration), as do examples 55 and 24.

Of these compounds 1 to 5, 8, 15 to 18 and 43 are preferred.

In the illustration of the above formulae, the CH₃ -groups are not givenin full. Compound 1 contains, for example, the (+)-camphorcarboxylicacid group as group R¹ --R¹¹.

The compounds according to the invention are valuable neurokinin(tachykinin)-antagonists which exhibit substance P-antagonism, but alsohave neurokinin A- and neurokinin-B antagonistic properties. They areuseful for treating and preventing neurokinin-mediated diseases such asrespiratory tract diseases e.g. asthma, bronchitis, rhinitis, cough orexpectoration as well as inflammatory eye diseases such asconjunctivitis, inflammatory skin diseases such as dermatitis andurticaria, inflammatory intestinal diseases such as ulcerative colitisor Crohn's disease, other inflammatory diseases such as polyarthritis orosteoarthritis as well as painful conditions (for e.g. migraine) andgastro-intestinal complaints such as irritable colon and vomiting.

Of special interest to medicine are compounds whose NK₁ - and NK₂ -values are of a similar order of magnitude.

The invention, therefore, also relates to the use of the compoundsaccording to the invention as drugs and pharmaceutical preparationscontaining these compounds. It is preferred if the compounds are usedfor human beings. They may be given intravenously, subcutaneously,intramuscularly, intraperitoneally, intranasally, inhalationally,transdermally, optionally assisted by iontophoresis or known enhancers,and orally.

For the parenteral administration, the compounds of formula I or thephysiologically compatible salts thereof are placed in solution,suspension or emulsion, optionally with the substances normally used forthis purpose such as solubilisers, emulsifiers or other excipients. Thesolubilisers used are for example: water, physiological sodium chloridesolutions or alcohols such as ethanol, propanediol or glycerin, sugarsolutions such as glucose or mannitol solutions or else a mixture ofdifferent solubilisers.

Furthermore, the compounds may be administered by implants, for exampleof polylactide, polyglycolide or polyhydroxybutyric acid or intranasalpreparations.

The compounds may be prepared using generally known methods of amino andpeptide chemistry, by condensing, step by step, the relevant amino acidsor peptide derivative part sequences, carboxylic or sulphonic acids andamines and isolating the compound thus obtained in free form or in theform of the desired salt.

The dipeptide derivatives of formula Ia

    R.sup.1 --R.sup.11 --A.sup.1 --A.sup.2 --NR.sup.2 R.sup.3  Ia

may be synthesised from the parts R¹ --R¹¹ OH, H--A¹ --OH, H--A² --OHand HN(R³)R², whereby the sequence of the couplings may be from right toleft, from left to right or by coupling the units R¹ --R¹¹ --A¹ --OH andH--A² --N(R³)R² (fragment couplings).

The compounds according to the invention may be prepared using generallyknown methods of peptide chemistry such as described in "Houben-Weyl,Methoden der organischen Chemie, Vol. 15/2", or using solid phasepeptide synthesis (e.g. R. C. Sheppard, Int. J. Pept. Prot. Res., 21,118 1983!) or similar known methods. Here, the relevant amino acids orpartial amino acid sequences are condensed step by step and theresultant peptides are isolated in free form or in the form of thedesired salts. The amino protecting groups used are those described in"Houben-Weyl, Methoden der organischen Chemie, Vol. 15/1", whereby thebenzyloxycarbonyl group (Z) is preferred in conventional syntheses andthe fluorenylmethoxycarbonyl group (Fmoc) in solid phase syntheses. Inthe case of the conventional synthesis the side chain of the argininewas protected by protonation, in the case of the solid phase synthesis,the Mtr-group was used. In the solid phase peptide synthesis thefollowing amino acids with protected side chains were, for example,used: Lys(Boc), His(Bum), Ser(tBu) and Asp(tBu). The specific synthesisconditions are apparent from the following Examples.

For the synthesis of the compounds of general formula I using the solidphase synthesis, those dipeptide carboxylic acids are initiallysynthesised which are reacted in solution to form dipeptide amides. Thefollowing anchor groups are suitable

1. Benzylester (G. Barang, R. B. Merrifield, Peptides 2, 1 (1980) Eds.E. Gross, J. Meienhofer, Academic Press, New York)

2. PAM-Anker (R. B. Merrifield, J. Am. Chem. Soc. 85, 2149 (1966))

3. Wang-Anker (S.-S. Wang, J. Am. Chem. Soc. 95, 1328 (1973))

4. SASRIN-Anker (M. Mergler, R. Tanner, J. Gostuli, P. Grogg, Tetrah.Lett. 29, 4005 (1988)).

For preparing the compounds of formula Ib

    R.sup.1 --R.sup.11 --A.sup.1 --R.sup.5                     Ib

the components R¹ --R¹¹ OH, the amino acid H--A¹ --OH and the amineH--R⁵ are bonded to one another. Optionally, the carboxylic acid of R¹--R¹¹ OH may first be coupled with a suitably protected form of H--A¹--OH and, following cleavage of the protecting group, condensed with theamine H--R⁵, or the suitably protected amino acid H--A¹ --OH may firstbe reacted with H--R⁵ and this product may be coupled with R¹ --R¹¹ OHafter deprotection.

The basic forms of the amines H--R⁵ may be obtained using known methods:

if H--R⁵ is ##STR29## with t=1 and u=0 and R⁶, Y and Z are ashereinbefore described, the preparation is carried out using knownmethods as described by A. L. Davis et al., J. Med. Chem. 18, 752 (1975)or H. Merz, DE 38 23 576 (C.A. 114 (21), 207 052 m). The introduction ofthe group R⁶ into a compound of general formula XI is carried out byreaction with NaH and BrR⁶. This reaction may take place in the presenceor absence of a protecting group (Sch) on the exocyclic N.

This preparation may be demonstrated by the following reaction scheme:##STR30##

Suitable protecting groups (Sch) are base-stable protecting groups suchas the Boc-group.

In order to prepare a compound of general formula XI, a compound ofgeneral formula X is cyclized under reductive conditions (e.g. analogousto the method described by A. L. Davis et al. (J. Med. Chem. 9, 826(1966)) by means of Pd-black).

The compound X may be prepared from the correspondingly substituted1-nitrobenzylalcohol (VII) and via the intermediary stages VIII and IX(by halogenation with e.g. SOCl₂ and subsequent reaction withacetamidomalonic acid diethylester according to J. Med. Chem. 9, 828(1966).

An amine H--R⁵ of general formula IIb ##STR31## wherein t=1 and u=0 andR⁶, Y and Z are as specified hereinbefore for formula IIa may beprepared by reduction of a corresponding compound IIa by means of e.g.LiAlH₄.

For preparing a compound IIa, wherein t=u=0 and R⁶, Y and Z are asspecified hereinbefore, the method according to A. L. Davis et al., J.Med. Chem. 16, 1043 (1973) is suitable. Here, starting fromα-bromo-o-nitrophenylacetic acid methylester, the phthalimido group isintroduced and after cleavage of the protecting groups and reduction ofthe nitro group, the cyclisation takes place to form (substituted orunsubstituted) 3-amino-2-indolinone: ##STR32##

The introduction of R⁶ and reduction to form the analogous compound ofgeneral formula IIb may be carried out as indicated above.

The preparation of compound IIa with t=2, u=0, wherein R⁶, Y and Z is asdefined above may be summarised by the following reaction scheme:##STR33##

The introduction of R⁶ and reduction to form the analogous compound IIbmay be carried out as indicated above.

When using this preparation method, the correspondingly substituted2-(2-nitrophenyl)-ethylbromide (XVIII) may be reacted withacetamidomalonic acid diethylester to form compound XIX and then XX,analogously to the methods described above.

The reduction of compound XX to form compound XXI may be carried outunder pressure in a solution of MeOH and water, for example by hydrogenin the presence of Pd-black. The cyclisation to prepare compound XXIImay be carried out with polyphosphoric acid whilst stirring and heating.

The preparation of compound IIa with t=u=1, wherein R⁶, Y and Z are asdefined above, may be carried out as follows: unsubstituted orsubstituted phthaloylphenylalanine is coupled with the amine H₂ N--R⁶and then cyclised with formaldehyde in a reaction of the Pictet-Spenglerkind. Finally, the phthaloyl group is cleaved off, for example bytreating with hydroxylamine: ##STR34##

The reduction to form the analogous compound of general formula IIb maybe carried out as indicated above.

The preparation of an amine HR⁵ of general formula IIIa ##STR35##wherein R⁶, Y and Z are as defined above may be carried out according toG-Leclerc et al., J. Med. Chem. 29, 2427 (1986). For this purpose,substituted or unsubstituted 3-bromoquinoline is first converted intothe corresponding N-oxide, then transposed to the quinolin-2-one andfinally the amino group is introduced with ammonia under pressure (inthe carrier tube): ##STR36##

The introduction of the substituents R⁶ may be carried out as describedabove with respect to compound IIa.

The preparation of a compound HR⁵ of general formula IVa ##STR37##wherein R⁶ is as defined above and R⁸ represents hydroxy and R⁹ ishydrogen, may be carried out according to R. Weichert, Arkiv Kemi 25,231 (1966). Here, acetaminomalonic acid monoethylether is reacted withsubstituted or unsubstituted 2-nitrobenzaldehyde, then it is hydrolysed,the nitro group is reduced and finally the cyclisation is carried out:##STR38##

The introduction of R⁶ is carried out as described above.

In order to prepare a compound IVa wherein R⁹ represents (C₁₋₅) alkoxy,phenyl-(C₁₋₅) alkyloxy, naphthyl-(C₁₋₅)alkyloxy or (C₁₋₄)alkylcarbonylor wherein R⁸ and R⁹ together represent oxygen or --OCH₂ CH₂ O--, theabove compound IVa wherein R⁸ represents hydrogen and R⁶ representshydroxy, may be reacted as follows:

a) for preparing a compound IVa, wherein R⁹ is alkyloxy, phenyl ornaphthylalkyloxy: etherication according to Williamson;

b) for preparing a compound IVa, wherein R⁹ is alkylcarbonyl; reactionwith the corresponding acid anhydride;

c) for preparing a compound IVa, wherein R⁸ and R⁹ together representoxygen: oxidation according to e.g. Oppenauer;

d) for preparing a compound IVa, wherein R⁸ and R⁹ both represent --OCH₂CH₂ O--: reaction of the keto compound obtained according to (c) withethyleneglycol.

In order to prepare amines of general formula H--R⁵, wherein R⁷ isalkyl, the compounds of general formula IIa, IIb, IIIa and IVa arealkylated. This alkylation may be carried out by protecting theexocyclic N initially by e.g. trifluoroacetyl, carrying out thealkylation with e.g. alkylbromide and then cleaving the protecting groupby e.g. hydrolysis.

Pharmaceutical Preparations:

    ______________________________________                                        Pharmaceutical Preparations:                                                  ______________________________________                                        Injection solution                                                            200  mg    active substance *                                                 1.2  mg    monopotassium dihydrogen phosphate                                            = KH.sub.2 PO.sub.4        (buffer)                                0.2  mg    sodium dihydrogen phosphate =                                                 NaH.sub.2 PO.sub.4.2H.sub.2 O                                      94   mg    sodium chloride                                                    or                         (isotonic)                                         520  mg    glucose                                                            4    mg    albumin         (protease protection)                               q.s.       sodium hydroxide solution                                                                        to adjust the pH to pH 6                       q.s.       hydrochloric acid                                                  sufficient water to make a 10 ml solution for injection purposes              Injection solution                                                            200  mg    active substance*                                                  94   mg    sodium chloride                                                    or                                                                            520  mg    glucose                                                            4    mg    albumin                                                             q.s.      sodium hydroxide solution                                                                         to adjust the pH to pH 9                       q.s.       hydrochloric acid                                                  sufficient water to make a 10 ml solution for injection purposes              Lyophilisate                                                                  200  mg    active substance*                                                  520  mg    mannitol (isotonic/structure builder)                              4    mg    albumin                                                            Solvent 1 for lyophilisate                                                    10   ml    water for injection purposes                                       Solvent 2 for lyophilisate                                                    20   mg    Polysorbat ®80 = Tween ®80                                            (surface-active substance)                                         10   ml    water for injection purposes                                       ______________________________________                                         *Active substance: compounds according to the invention, for example the      compound of Example 1 or 201.                                                 Dosage for human beings of 67 kg: 1 to 500 mg                            

EXAMPLE 1tert.-Butyloxycarbonyl-(2S)-2-naphthylalanyl-(2-methoxyphenyl)piperazide(I)

3.15 g of tert.-Butyloxycarbonyl-L-2-naphthylalanine and 1.8 g ofN,N'-Carbonyldiimidazole were stirred in 100 ml of THF for 2.5 hours.1.93 g of 1-(2-Methoxyphenyl)piperazine were added, stirred for 12 hoursat ambient temperature and then the THF was distilled off in vacuo. Thenthe mixture was taken up in 100 ml of ethyl acetate, extracted with 10%KHCO₃ -solution and water, the ethyl acetate phase was dried over Na₂SO₄ and concentrated in vacuo.

4.9 g of colourless oil

tert.-Butyloxycarbonyl-(2S,4R)-4-hydroxyprolyl-(2S)-2-naphthylalanyl-(2-methoxyphenyl)-piperazide(II)

4.9 g of I were stirred in 50 ml of trifluoracetic acid/dichlormethane(1:1) for 45 minutes at ambient temperature, the solution wasconcentrated by evaporation in vacuo, the residue was dissolved in ethylacetate and extracted twice with 10% KHCO₃ solution and twice withwater, the ethyl acetate phase was dried and concentrated byevaporation. The oily residue was dissolved in 50 ml ofDMF/Dichloromethane (1:1) and mixed with 2.3 g of tert.-Butyloxycarbonyl(2S,4R)-4-hydroxyproline, 1.6 g of 1-Hydroxybenzotriazole, adjusted topH 9.5 with 3 ml of Diisopropylethylamine, and then 3.8 g ofTetramethyluronium tetrafluoroborate were added and the mixture wasstirred for 24 hours. The solution was concentrated by evaporation inhigh vacuum, the residue was taken up in ethyl acetate and extractedtwice with 10% KHCO₃ solution and twice with saturated NaCl-solution,dried and concentrated by evaporation.

5.4 g of yellow oil (90% of theory).

(+)-Camphor-3-carbonyl-(2S,4R)-4-hydroxypropyl(2S)-2-naphthylalanyl-(2-methoxyphenyl)piperazide (1) ##STR39##

0.6 g of II were stirred with 20 ml of Trifluoraceticacid/Dichloromethane (1:1) for 45 minutes at ambient temperature,concentrated by evaporation and taken up in ethyl acetate, extractedwith 10% KHCO₃ -solution and water, dried and concentrated byevaporation. The residue was taken up in 40 ml of DMF/Dichloromethane(1:1), mixed with 0.2 g (+)-Camphor-3-carboxylic acid, 0.16 g of1-Hydroxybenzotriazole, 1 ml of Diisopropylethylamine and 0.38 g ofTetramethyluronium tetrafluoroborate and stirred for 12 hours at ambienttemperature. After concentration, the mixture is taken up in ethylacetate, extracted twice with 10% KHCO₃ solution and twice with water,dried and concentrated by evaporation. The hydrochloride salt isprecipitated by the addition of ethereal HCl.

310 mg (45 % of theory).

EXAMPLE 2 ##STR40## EXAMPLE 2

Preparation of 2a:

7.0 g of Boc-L-Tryptophan (23 mMol) and 3.1 g ofN-Methyl-(o-methylbenzyl)-amine (23 mM) were dissolved in 200 ml of DMF,mixed with 7.75 g of TBTU (24 mM) and adjusted to about pH 8 by adding afew drops of Triethylamine. After 24 hours at ambient temperature, themixture was concentrated to dryness in vacuo, the residue was taken upin 300 ml of ethyl acetate, extracted 3 times with 150 ml of 0.5n HCleach and 3 times with 150 ml of NaHCO₃ solution each. The ethyl acetatephase was dried with MgSO₄, filtered and concentrated to dryness,yielding 7.4 g of 2a as an ivory-coloured solid substance. M.p.: 70°-84°C.

α!_(D) ²⁰ =34.3° (MeOH)

Preparation of 2b:

6.8 g of 2a (16 mM) were mixed with 200 ml of 4n HCl in Dioxane andstirred for 1 hour at ambient temperature. The reaction solution wasconcentrated to dryness, the residue was stirred with ether, suctionedoff, washed with ether and dried in a desiccator. 6.47 g ofhydrochloride 2b were obtained as a pink powder.

Preparation of 2c:

4.5 g of 2b (12.6 mM) and 2.91 g of Boc-(2S,4R)-Hydroxyproline weredissolved in 120 ml of DMF, mixed with 4.3 g of TBTU (13.4 mM) andadjusted to a pH value of about 8 by adding TEA. After 24 hours ofstirring at ambient temperature, the mixture was concentrated todryness, taken up in 400 ml of ethyl acetate, extracted 3 x with 200 mlof 0.5n HCl and 3 times with 200 ml of 1n NaHCO₃ solution each, and theorganic phase was dried over MgSO₄ filtered and concentrated byevaporation. 6.33 g of 2c were obtained as a cream coloured solidsubstance.

Preparation of 2d:

The Boc-protecting group was cleaved in the way as described underPreparation of 2b. Here, 4.7 g of the hydrochloride 2d was obtained as acream-coloured powder.

Preparation of 2e:

1.2 g of 2d (2,55 mM) and 0.5 g of (+)-Camphorcarboxylic acid (2.55 mM)were combined with 30 ml of CH₂ Cl₂ and 0.9 g of TBTU (2,8 mM), adjustedto pH 8 by adding TEA and stirred for 24 hours at ambient temperature.The reaction mixture was concentrated to dryness and the residue waschromatographed over silica gel using CH₂ Cl₂ /MeOH=9:1 as eluent. Thecombined fractions were concentrated yielding 0.49 g of 2e as acream-coloured solid substance:

M.p.: 55°-64° C.

α!_(D) ²⁰ =-21.4° (MeOH)

EXAMPLE 3 (Compound 34)

Compound 2d TBTU (-)-Camphorcarboxylic acid ##STR41##

The synthesis of 2d was carried out as in Example 2. 0.63 g of 2d (1.34mMol) and 0.26 g (-)-Camphorcarboxylic acid were dissolved in 25 ml ofDMF, the pH value was adjusted to 8 by adding 0.38 ml of TEA, and 0.48 gof TBTU were added. The preparation mixture was stirred overnight atambient temperature and then concentrated to dryness on the rotaryevaporator. The residue was dissolved in ethyl acetate andchromatographed over silica gel with ethyl acetate as mobile solvent.Here, the above compound was obtained as a white solid substance. Yield:0.46 g.

M.p.: 125°-144° C.; α!_(D) ²⁰ =-81 9° (MeoH)

The other compounds of this invention may be prepared analogously, forexample the above mentioned compounds 1 to 53.

List of the physical data of Compounds 1 to 56.

    ______________________________________                                        Compound      Mp  °C.!                                                 ______________________________________                                        1             159-164                                                         2             55-64                                                           3             138-148                                                         4             148-152                                                         5             160-170  decomposition                                          6             178-184                                                         7             140-145                                                         8             145-155                                                         9             245-250                                                         10            182-186                                                         11            120-128                                                         12            165-176  decomposition                                          13            175-180                                                         14            200-215                                                         15            140-144  decomposition                                          16            141-145                                                         17            155-160                                                         18            160-165                                                         19            130-135  decomposition                                          20            143-147  decomposition                                          21            163-167                                                         22            194-197                                                         23            125-129  decomposition                                          24            140-148                                                         25            solid oil                                                       26            138-146                                                         27            72-76                                                           28            132-138                                                         34            125-144                                                         42            139-143                                                         43            124                                                             44            134-136                                                         45            111-118                                                         46            120-142                                                         47            120-140                                                         48            108-110                                                         55            132-136                                                         56            118-123                                                         ______________________________________                                    

What is claimed is:
 1. An amino acid derivative of formula I:

    R.sup.1 --R.sup.11 --A.sup.1 --B

or the pharmaceutically acceptable salts thereof, wherein R¹ is selectedfrom the group consisting of ##STR42## R¹¹ is --C(O)--; A¹ is selectedfrom the group consisting of a proline radical and a 4-hydroxyprolineradical wherein the proline or hydroxyproline radical is attached to R¹¹by way of the ring nitrogen and is attached to B by way of side chaincarbonyl; B is the group --A² --NR² R³ ; A² is selected from the groupconsisting of ##STR43## Y' is selected from the group consisting of Hand CH₃ ; R² and R³ are independently selected from the group consistingof alkyl, arylalkyl, heteroaryl and hydroxy (wherein aryl is selectedfrom the group consisting of phenyl; mono-, di- or tri-substitutedphenyl; and naphthyl, wherein the phenyl substituents are independentlyselected from the group consisting of halogen, trihalomethyl, alkoxy,alkyl, alkylthio, hydroxy, nitro, trifluoromethoxy, dialkylamino andcyano, or two adjacent positions of the phenyl group are linked by--O-(CH₂)₁ or 2 --O--; heteroaryl is selected from the group consistingof indolyl, pyridyl, pyrrolyl, imidazolyl and thienyl; and the alkyl andalkoxy groups have from one to three carbon atoms).
 2. The amino acidderivative according to claim 1, wherein R² and R³ are independentlyselected from the group consisting of alkyl, arylalkyl, heteroaryl andhydroxy (wherein aryl is selected from the group consisting of phenyl;mono-, di- or tri-substituted phenyl; or naphthyl, wherein the phenylsubstituents are independently selected from the group consisting ofhalogen, trihalomethyl, alkoxy, alkyl and cyano; heteroaryl is selectedfrom the group consisting of indolyl, pyridyl, pyrrolyl, imidazolyl andthienyl; and the alkyl and alkoxy groups have from one to three carbonatoms).
 3. The amino acid derivative according to claims 1 or 2, whereinR¹ is ##STR44##
 4. The amino acid derivative according to claim 1,wherein A¹ is a 4-hydroxyproline radical with 2-S configuration.
 5. Theamino acid derivative according to claim 1, wherein A² is in theS-configuration.
 6. The amino acid derivative according to claim 5,wherein A² is selected from the group consisting of ##STR45## and Y' isselected from the group consisting of H and methyl.
 7. The amino acidderivative according to claim 6, wherein A² is ##STR46##
 8. The aminoacid derivative according to claim 1, wherein R² is alkyl and R³ isarylalkyl (wherein aryl is selected from the group consisting of phenyland mono-, di- or tri-substituted phenyl; wherein the phenylsubstituents are independently selected from the group consisting ofhalogen, trihalomethyl, alkoxy, alkyl and cyano; heteroaryl is selectedfrom the group consisting of indolyl, pyridyl, pyrrolyl, imidazolyl andthienyl; and the alkyl and alkoxy groups have from one to three carbonatoms).
 9. The amino acid derivative according to claim 8, wherein thesubstituent on the phenyl is in the 2-position.
 10. The amino acidderivative according to claim 8, wherein R³ is unsubstituted benzyl orbenzyl monosubstituted with halogen or alkyl.
 11. The amino acidderivative according to claim 10, wherein R² is methyl and R³ is2-methylbenzyl.
 12. An amino acid derivative having the formula:##STR47##
 13. A pharmaceutical composition comprising the amino acidderivative according to any one of claims 1-12 and a pharmaceuticallyacceptable carrier.